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US20040063612A1 - Neuroprotective agents - Google Patents

Neuroprotective agents Download PDF

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US20040063612A1
US20040063612A1 US10/672,257 US67225703A US2004063612A1 US 20040063612 A1 US20040063612 A1 US 20040063612A1 US 67225703 A US67225703 A US 67225703A US 2004063612 A1 US2004063612 A1 US 2004063612A1
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arginine
mammal
iii
glutamate
pga
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Manssur Yalpani
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CarboMer Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to neuroprotective compounds, methods for preventing and treating neurodegenerative diseases and therapeutic compositions that contain said compounds, derivatives or pharmaceutically acceptable salts as active ingredients.
  • the neuroprotective compounds of the present invention inhibit nitric oxide synthases and exhibit a neuroprotective activity and are useful as therapeutics of neurological diseases.
  • Apoptosis or programmed cell death may arise from stroke, heart attack or other brain or spinal chord ischemia or trauma.
  • apoptosis is linked to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease (PD), Pick's disease and Creutzfield-Jacob disease (Esiri M., Morris J. E. The Neuropathology of Dementia, 1997).
  • Apoptosis involves nuclear and cytoplasmic shrinkage and DNA fragmentation. Cysteine proteases known as caspases trigger DNA degradation. Nitric oxide synthases (NOSs) oxidize of L-arginine to citrulline, generating nitric oxide (NO), which is implicated in apoptosis. Of the three known NOSs, two (NOS I and NOS III) synthesize NO in CNS neurons. Elevated NO levels have both beneficial and detrimental effects on CNS cell viability and function. NO's detrimental effects result from its reaction with superoxide anion that generates the oxidant peroxynitrite (ONOO), which causes DNA strand breaks.
  • NOOSs oxidant peroxynitrite
  • NOS inhibition can be abrogated by NOS inhibition, free radical scavengers, growth factor repletion following injury or genetic depletion of the NOS I gene.
  • Brains of AD patients display abnormal NOS III gene expression and apoptosis likely represents an important pathogenic mechanism of neurodegeneration. Neuronal loss and synaptic disconnection cause cognitive impairment in AD and other neurodegenerative disorders.
  • AD Alzheimer's disease
  • ischemic stroke targets clots in blocked blood vessels and is suitable for only a very small number of patients. No approved treatment exists for the remaining patients suffering the most severe strokes.
  • AD cholinesterase inhibitors
  • neuroprotective agents such as amino acid and peptide derivatives (Findeis M A, Curr. Top. Med. Chem., 2, 417-23, 2002), e.g., the tripeptide pGlu-Glu-Pro-NH 2 (Koenig et al., Peptides, 22, 2091-7, 2001), D-cycloserine (Tsai et al., Am. J. Psychiatry, 156, 467-9, 1999), activity-dependent neurotrophic factor, Posatirelin (Zamostiano et al., Neurosci.
  • amino acid and peptide derivatives e.g., the tripeptide pGlu-Glu-Pro-NH 2 (Koenig et al., Peptides, 22, 2091-7, 2001), D-cycloserine (Tsai et al., Am. J. Psychiatry, 156, 467-9, 1999), activity-dependent neurotrophic factor, Posatirelin (Zamostiano e
  • Proposed NOS inhibitors include 2-imino-4-methylpiperidine (Webber et al., J. Med. Chem., 41, 96-101, 1998), N6-(1-iminoethyl)-L-lysine (Stenger et al., Eur. J.
  • arginine analogues e.g., monomethyl-L-arginine (Southan, G. J., Szabo, C., Biochem. Pharm., 51, 383-394, 1996).
  • Certain poly(amino acids) are reported to stimulate outgrowth of cultured neurites and induce the formation of neuronal networks (Hefti et al., Brain Res., 541, 273-83, 1991).
  • Administration of general NOS inhibitors is impractical and possibly dangerous, since NO has important effects on cerebral circulation. While high NOS levels may be toxic to some neurons, other neurons require it for survival.
  • Amyloid ⁇ -peptide (A ⁇ ) is the major constituent of extracellular plaques and amyloid deposits. Other metals, however, may offer neuroprotection in dementia and ischaemic stroke. Thus, magnesium exhibits a range of neuronal activities that may ameliorate ischaemic CNS insults, including stroke (Muir K W., CNS Drugs, 15, 921-30, 2001). Significant neuroprotection with Mg is observed in cerebral ischaemia, with infarct volume reductions of 25-61%. Lithium (De-Maw Chuang, Ann. N.Y.
  • the neuroprotective compounds of the present invention are administered to mammals in amounts effective to inhibit nitric oxide synthase enzymes (NOS) and in particular NOS III.
  • NOS nitric oxide synthase enzymes
  • a gamma-polyglutamate is employed in a method to inhibit NOS in a mammal.
  • the molecular weight of the ⁇ -PGA is from about 100,000 to about 7,000,000 Daltons and is usually from about 250,000 to about 2,000,000. Preferably, the molecular weight of the ⁇ -PGA is about 1,000,000 Daltons.
  • the ⁇ -PGA can be made by the fermentation of Bacillus licheniformis and fractionated to make a monodisperse ⁇ -PGA. The monodisperse ⁇ -PGA is used to inhibit NOS III and treat neurodegenerative diseases such as Alzheimer's disease and stroke.
  • the present invention relates to the neuroprotective compounds (Formulas I-IV and XII and other compounds described herein) and methods for preventing, slowing the progression of and treating neurodegenerative diseases, cerebral infarction [cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction (atherothrombotic infarction, lacunar infarction and cardiogenic embolism)], transient ischemic attack and cerebral edema, traumatic brain injury, spinal injury, pain [headache (migraine, tension headache, cluster headache and chronic paroxysmal headache)], Parkinson's disease, Alzheimer's disease, seizure, disorders of the central nervous system, mood and emotional disorders, anxiety and psychosis, substitution therapy, morphine tolerance or dependence; thyroid disease, neuroendocrine disorders and dysregulation of food intake, disorders of nociception and pain control; autonomic disorders, cardiovascular dysfunction, co-medication in surgical procedures; septic shock, chronic rheumatoid arthritis, osteoarthritis
  • neuroprotective compounds of the present invention include compounds of general formulas I to II below:
  • the neuroprotective compounds of the present invention furthermore include arabinogalactan compounds of general formula III below:
  • arabinogalactans encompassed by this invention are derived from acacia (gum arabic), and constitute complex, branched arabic acid derivatives (molecular weight from about 10,000 to about 2,000,000, preferably from about 100,000 to about 500,000 and most preferably about 250,000 Da) with a 1,3- ⁇ -D-galactose backbone with O-6 linked branches composed of D-galactose, L-arabinofuranose and D-glucuronic acid units bearing additional L-rhamnose branches.
  • novel neuroprotective compounds of the present invention furthermore include compounds of general formulas IV and XII below:
  • Z, Z 1 , Z 2 , Z 3 (CH 2 ) p , C ⁇ O, CHO, N, NH, C ⁇ CHR 1 , CH—NH, C ⁇ NNH, O, S
  • R 1 , R 2 , R 3 (CH 2 ) k R 4 , O(CH 2 ) k R 4 , OH, carbohydrate, amino acid, (trishydroxymethyl)aminomethane,
  • R 4 H, alkyl, fluorine, halogen, N-alkyl, (trishydroxymethyl)aminomethane
  • W CH 2 , CH 2 R 5 , CH, CHR 5 , N(R 5 ) j , N, O, S, C ⁇ O
  • R 5 H, F, OH, alkyl, aryl and
  • novel neuroprotective compounds of the present invention furthermore include polymeric metal complexes of general formulas XII below:
  • P is an anionic polymer, including a polysaccharide, oligosaccharide, polypeptide, poly(amino acid), or synthetic polymer
  • M is a metal ion that plays a neuroprotective role, such as aluminum, calcium, copper, lithium, magnesium, manganese, selenium, iron and zirconium.
  • the compounds of Formula XII include both salts and complexes.
  • polymeric metal complexes include polysaccharide iron complexes and poly(glutamic acid) iron complexes where the poly(amino acid) includes compounds of general formulas I and II of this invention, and the oligosaccharide and polysaccharide may be derived from alginate, arabinogalactan, cellulosics, e.g., carboxymethyl cellulose, dextran, galactomannan, konjac, maltodextrin, pectin, starch, starch glycolic acid, oxyamylose, oxycellulose, chondroitin sulfate, dextran sulfate, dextran phosphate, gellan and xanthan, and certain polynucleotides, e.g., polycyticyclic acid, polyinosinic acid, polyxenyl phosphate and where the synthetic polymer contains carboxylic acid, phosphate or sulfate functions, e.g., polyvinyl
  • Polymers based on acrylic acid, maleic anhydride and methacrylic acid are particularly preferred, as are cross-linked polyacrylic acid, poly(acrylic acid-isobutyl vinyl ether and copolymers of acrylic acid and dimethylaminoethylacrylate).
  • the molecular weight ranges from 1,000 to 10 million, preferably from 10,000 to 5 million, and most preferably 40,000 to 1 million Daltons.
  • novel neuroprotective compounds of the present invention furthermore include additional compounds as described herein (in addition to the compounds of Formulas I-IV and XII) and extracts and actives derived from extracts of certain natural products, such as cranberry, blueberry, red sour cherry, tea and elderberry.
  • FIG. 1 shows the structures of ⁇ -PGA and ⁇ -PGA.
  • FIG. 2 is an SEC/MALLS chromatogram of a commercial sample of ⁇ -PGA (obtained with 13.24 mg ⁇ -PGA, a Waters Ultrahydrogel 250 column and with 0.1 M citrate buffer (pH 2.0) as eluent).
  • FIG. 3 is a 3-dimensional SEC/MALLS chromatogram of the high molecular weight ⁇ -PGA prepared in Example 1.
  • FIG. 4 show an SEC elution peak of fractionated ⁇ -PGA from the MALLS detector II.
  • the narrow peak distribution is indicative of a monodisperse material.
  • Analysis confirmed that the P D of the material was 1.0 with a molecular weight of 300,000 Da.
  • FIG. 5 is a graph showing the change in neuronal viability as a function of ⁇ -PGA concentration.
  • FIG. 6 is a graph showing the change in neuronal viability as a function of arabinogalactan concentration.
  • FIG. 7 is a graph showing the change in neuronal viability as a function of ⁇ -PGA concentration.
  • FIG. 8 is a graph showing the change in neuronal viability as a function of arabinogalactan concentration.
  • FIG. 9 is a graph showing the change in neuronal viability as a function of diphenylamine concentration.
  • FIG. 10 is a graph showing the change in mitochondrial function as a function of increasing multiplicity of adenovirus infections produced by a treatment with ⁇ -PGA.
  • FIG. 11 is a graph showing the change in mitochondrial function as a function of increasing multiplicity of adenovirus infections (MOI) by a treatment with dichlorobenzhydrol phenoxyamine.
  • FIG. 12 is a graph showing the change in mitochondrial function as a function of increasing multiplicity of adenovirus infections (MOI) by a treatment with arabinogalactan.
  • one or more compounds of Formulas I-IV, XII and/or the other compounds described herein are administered to mammals to treat the neurodegenerative disorders described herein.
  • the compounds are administered in an amount effective to inhibit one or more nitric oxide synthase enzymes in the mammal.
  • Pharmaceutically acceptable salts and esters of the neuroprotective compounds are also employed in practicing the present invention.
  • one or more compounds of Formulas I-IV, XII and/or the other compounds described herein are administered to a human at a high risk of developing Alzheimer's disease to prevent or slow down its onset or a patient already diagnosed with Alzheimer's disease to slow its progression and/or to reverse its effects (collectively referred to as treating Alzheimer's disease).
  • Preferred compounds of the present invention for the treatment of Alzheimer's disease are the gamma-polyglutamate ( ⁇ -PGA) polymers preferably made by a biological process, such as, for example, the fermentation of Bacillus licheniformis .
  • the molecular weight of the ⁇ -PGA is from about 100,000 to about 7,000,000 Daltons and is usually from about 250,000 to about 2,000,000.
  • the molecular weight of the ⁇ -PGA is about 1,000,000 Daltons.
  • the ⁇ PGA can be fractionated to make a monodisperse ⁇ -PGA. See FIG. 4.
  • the ⁇ -PGA can be fractionated employing standard techniques.
  • monodisperse ⁇ -PGA is meant ⁇ -PGA having a polydispersity of less than about 1.3, advantageously less than about 1.2 and preferably less than about 1.1.
  • a ⁇ -PGA composition is made that is monodisperse having a P D of about 1.0.
  • the present invention is directed to the treatment of an apoptosis-mediated disease in a mammal, which comprises administering one or more compounds of Formulas I-IV, XII and/or the other compounds described herein in an amount that inhibits apoptosis.
  • the present neurodegenerative compounds described herein are employed to treat any disease state in a mammal that involves elevated nitric oxide synthase levels (NOS) and in particular NOS III.
  • NOS nitric oxide synthase levels
  • the present neurodegenerative compounds are administered in an amount that inhibits NOS activity.
  • arabinogalactan is employed as the neuroprotective agent.
  • Arabinogalactan a water-soluble polysaccharide that can be isolated from species of the genus Larex.
  • Arabinogalactan is highly soluble and can be obtained at 95% purity from larch chips.
  • refined arabinogalactan of above 95% or 99.9% purity is used as neuroprotective agent.
  • the preparation of this material is disclosed in U.S. Pat. No. 5,116,969 and it is available from Larex, International, St. Paul, Minn.
  • Arabinogalactan is highly stable, non-toxic, and non-immunogenic.
  • arabinogalactan includes naturally occurring or synthetic arabinogalactan, fragments of arabinogalactan, such as degradation products, and modified arabinogalactan or fragments thereof that have been modified using methods available in the art.
  • refined arabinogalactan refers to arabinogalactan with a purity greater than 95%. The molecular weight of arabinogalactan ranges from about 6,000 to 2,500,000 Daltons and for the refined arabinogalactan about 10,000-30,000 Daltons.
  • Arabinogalactans derived from larch comprise predominantly a 1,3- ⁇ -D-galactan backbone with 1,6- ⁇ -D-galactobiose, 1,3- ⁇ -L-arabinofuranosyl- ⁇ -L-arabinofuranose, and ⁇ -L-arabinofuranose branch units and L-arabinose:D-galactose ratios of 1.6 to 1.7 (see Whistler R. L., Industrial Gums Whistler R. L. ed., p. 304, Academic Press, New York, 1993.).
  • arabinogalactans are derived from acacia (gum arabic), and constitute complex, branched arabic acid derivatives (molecular weight of 250,000 to seven million Da) with a 1,3- ⁇ -D-galactose backbone with O-6 linked branches composed of two to five 1,3- ⁇ -D-galactosyl residues, ⁇ -L-arabinofuranose and 4-O-methyl- ⁇ -D-glucuronic acid units bearing additional L-rhamnose branches (see Whistler R. L., ibid., p. 311-318).
  • Arabinogalactan formulations can be provided, for example, in the form of a sterile 50% solution diluted in a buffered isotonic salt solution and this solution can then either be used directly or mixed with DMSO.
  • a sterile 50% solution diluted in a buffered isotonic salt solution can then either be used directly or mixed with DMSO.
  • the preparation of endotoxin-free arabinogalactan has been described in U.S. Pat. No. 5,589,591.
  • Thermally derived poly(aspartic acid) is furthermore a copolymer of D- and L-isomers, containing both ⁇ - and ⁇ -peptide bonds in the main chain (H. Pivcova, V. Saudek, J. Drobnik and J. Vlasak, Biopolymers, 20, 1605, 1981.).
  • Chemical polymerization of amino acid carboxyanhydrides on the other hand involves highly toxic chemicals, such as phosgene (W. D. Fuller, M. S. Velander and M. Goodman, Biopolymers, 15, 1869, 1976.), organic solvents and catalysts (H.
  • a ⁇ -polyglutamate is employed as the neuroprotective agent.
  • Various Bacillus species e.g., B. licheniformis
  • ⁇ -PGA linear poly( ⁇ -glutamic acid)
  • ⁇ -PGA linear poly( ⁇ -glutamic acid)
  • ⁇ -PGA assumes an ⁇ -helix conformation in solution, and, unlike the synthetic ⁇ -analogs, is a well-defined high molecular weight homopolymer.
  • a further unique feature is that ⁇ -PGA's composition can be varied from predominantly D- ⁇ -PGA (>95%) to predominantly L- ⁇ -PGA (>95%) by adjusting reaction conditions (e.g., by adjusting Mg concentrations). This allows for the additional control of biodegradability and other properties.
  • ⁇ -PGA is of particular interest for biomedical uses, due to its biocompatible, biodegradable (it degrades to glutamic acid), non-toxic, and non-immunogenic nature (R. H. De Kruyff, S. T. Ju, M. E. Dorf, Eur.
  • ⁇ -PGA derived by fermentation can display molecular weights of up to 7,000,000 Da based on GPC/MALLS data (S. S. Mark, T. C. Crusberg, M. Yalpani, A. Dilorio. AIChE Annual Meeting , Los Angeles, October, 1997).
  • M w ⁇ -PGA constitutes a milestone in poly(amino acids) technology and is of substantial interest and potential benefit for biomedical applications.
  • PGA is also amenable to facile processing, as its solution viscosity can be substantially reduced by co-solutes, if required.
  • Narrow molecular weight PGA fractions offer additional advantages.
  • polyglutamate can be used as a stool softener in a laxative composition.
  • laxative is meant to include bulk laxatives (the various soluble and insoluble fibers), stool softeners (such as dioctyl sulfosuccinates) and stimulant laxatives (such as phenolphthalein and senna).
  • a preferred polyglutamate is ⁇ -PGA.
  • the ⁇ -PGA can have a molecular weight of from about 100,000 Daltons to about 7,000,000 Daltons and is usually from about 250,000 to about 2,000,000 Daltons. A preferred molecular weight of the ⁇ -PGA is about 1,000,000 Daltons.
  • the PGA is administered orally at a dose of 50 mg to about 1 gram or more. Usual doses are between 100 mg and 500 mg and a preferred dose is between 200 mg and 300 mg.
  • the PGA can be administered alone or can be co-administered with bulk laxatives or stimulant laxatives. Preferably, the PGA is co-administered with one or more bulk laxatives either separately or in a composition that contains both the PGA and bulk laxative.
  • the present PGA may also be combined with other stool softeners such as salts of dioctyl sulfosuccinate. Preferred salts include the sodium, calcium and potassium salts of dioctyl sulfosuccinate.
  • Bulk laxatives useful for co-administration with the present PGA include psyllium, calcium polycarbophil, brans (such as wheat bran, oat bran, rice bran, etc), malt soup extract, karaya, guar gum, methylcellulose and mixtures of the various fibers.
  • Preferred bulk laxatives include psyllium, sodium methylcellulose, calcium polycarbophil, polycarbophil and mixtures thereof.
  • a particularly preferred bulk laxative is ground psyllium husks such as commercially available METAMUCIL.
  • the psyllium husks are preferably milled to a particle size where no more than 4% passes through a 100 mesh screen and 25% to 50% pass through a 200 mesh screen. Psyllium husk particle size ranges for use as a bulk laxative are described in U.S. Pat. No. 5,149,541 which is incorporated herein by reference.
  • the laxative compositions of the present invention may be any oral dosage form including, but not limited to, drink mixes, powders, capsules, tablets, and any kind of food or liquid incorporating the active ingredient(s) therein.
  • a dosage form selected from the group consisting of powdered drink mix, a wafer, a cookie and a food bar.
  • Optional ingredients to be added to these dosage formulations are well known to one of ordinary skill in the art.
  • Such optional ingredients include sweeteners, flavoring agents, flow agents, starches, dextrin, maltodextrins, inert carriers, dispersants, emulsifiers, food colors and the like.
  • Sweeteners include aspartame, sugar, saccharin, acesulfame K, sucralose and mixtures thereof. Laxative compositions and there preparation are described in U.S. Pat. No. 5,516,524 which is incorporated herein by reference.
  • a laxative composition of the present invention that contains ⁇ -PGA having a molecular weight of about 1,000,000 Daltons and ground psyllium husks would contain the following active ingredients: Ground psyllium husks 5 gm ⁇ -PGA 250 mg
  • the laxative composition is made with ground psyllium husks as described in U.S. Pat. No. 5,149,541 and then processed with maltodextrin and citric acid as described in U.S. Pat. Nos. 4,459,280 and 5,219,570 both of which are incorporated herein by reference.
  • a preferred sweetener is aspartame or a mixture of aspartame with acesulfame-K, saccharin and/or sucralose.
  • a mixture of various bulk laxatives are substituted for the ground psyllium husks in the laxative composition described above in similar proportions with the ⁇ -PGA.
  • the bulk laxative mixture can contain two or more of the following bulk laxatives: ground psyllium husks, oat bran, rice bran, wheat bran, polycarbophil, calium polycarbophil, malt soup extrtact, karaya, guar gum and methylcellulose.
  • tripeptides are employed as the neuroprotective agent.
  • Tripeptides are prepared employing procedures well known to one of ordinary skill in the art.
  • the tripeptides encompassed under this invention include: arginine-glutamate-arginine, arginine-asparagine-arginine, lysine-glutamate-arginine, arginine-glutamate-lysine, ornithine-glutamate-arginine, arginine-glutamate-ornithine, citrulline-glutamate-arginine, arginine-glutamate-citrulline, N-acetyl-arginine-glutamate-arginine, arginine-glutamate-arginine-NH 2 , arginine-glutamate-arginine-OCH 3 , D-arginine-L-glutamate-arginine, L-arginine-D-glutamate-arginine and L-argin
  • bridged aromatic compounds described by general formula IV [Y—(X) m —R] are employed as the neuroprotective agent.
  • the bridged aromatic compounds under this invention include: 4,4′-dichlorobenzydryl chloride, diphenylamine, 4-diphenylmethylene N-trifluoracetylpiperidine and Tamoxifen.
  • Compositions of this invention are obtained from suitable precursors by established etherification, amination, reductive amination, or equivalent substitution reaction procedures known to those skilled in the art. Representative preparations of benzophenone-containing compositions are given below.
  • compositions containing the benzophenone moiety are prepared by conversion of the latter via borohydride reduction in alcohol solution to 1,2-bis(phenyl phenylmethoxy)ethane.
  • the resulting benzhydrol (1 equivalent) is subsequently condensed with a suitable bifunctional alcohol or diol (e.g., ethylene glycol, 10 equivalents) in the presence of methanesulfonic acid catalyst to afford, after chromatography the corresponding ether or diether.
  • a suitable bifunctional alcohol or diol e.g., ethylene glycol, 10 equivalents
  • metal complexes and salts of biopolymers and synthetic polymers are employed as the neuroprotective agent.
  • the polymer metal complexes under this invention include: polysaccharide iron complexes and ⁇ -polyglutamate metal complexes. Additionally encompassed as part of the present invention are the following compounds that are also useful in the treatment of neurodegenerative diseases as disclosed herein:
  • Step 1 Coupling to solid support. Arginine, glutamate and asparagine (5 equivalents) were each reacted separately with the Wang resin (0.8 mmol/g) using HATU (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 5 eq) and DIEA (N,N-Diisopropylethylamine, 10 equivalents) as the coupling reagent and DMF/CH 2 Cl 2 (1/1) as solvent. After 18 h shaking, the solid was washed with DMF (3 times), CH 2 Cl 2 (4 times), MeOH (2 times) and ether (2 times), and dried under vacuum.
  • HATU 3-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 5 eq
  • DIEA N,N-Diisopropylethylamine
  • Step 2 Removal of Fmoc protecting group.
  • the solid was treated with a solution of 20% piperidine in DMF (1 mL), shaken for 45 minutes then washed and dried under vacuum.
  • Step 3 Peptide coupling. The above two-step sequence was repeated twice with the product from Step 2 and the appropriate amino acids to give 27 tripeptides on the solid support.
  • Step 4 Cleavage from solid support.
  • Each peptide was cleaved from the support by treatment with TFA/M 2 O/triethylsilane (95:2.5:2.5) for 2 h.
  • the solution was collected, the solid is washed with TFA (2 times) and these washes were added to the solution.
  • This solution was cooled in an ice bath and treated with ether, and the solid was extracted with water (2 mL and 1 mL). The combined water layer was washed with ether (3 times) and freeze-dried to give the desired tripeptide.
  • the products were identified by LC-Mass analysis.
  • Bacillus licheniformis ATCC 9945 from 1 mL freezer stocks was inoculated into starter medium (50 mL, 10 g/L peptone, 2 g/L yeast extract, 0.02 g/L MgSO 4 .7H 2 O.) and cultured to an absorbance (at 600 nm) of 1.0-1.5, ⁇ 8 h, to inoculate starter cultures for fermentations.
  • starter medium 50 mL, 10 g/L peptone, 2 g/L yeast extract, 0.02 g/L MgSO 4 .7H 2 O.
  • licheniformis ATCC 9945 cryovial was added to 250 mL (seed culture) production medium: 80 g/L glycerol, 50 g/L citric acid H 2 O, 50 g/L L-glutamic acid, 8.63 g/L NH 4 SO 4 , 0.5 g/L K 2 HPO 4 , 0.5 g/L MgSO 4 7H 2 O, 0.08 g/L MnSO 4 H 2 O, and 0.15 g/L CaCl 2 2H 2 O, pH adjusted to 7.0 with NaOH. Seed culture was added to a New Brunswick Bioflo III containing production medium (5 L) at a ratio of 4%.
  • the fermentation conditions were: dissolved oxygen (D.O.) 5%, temperature 37° C., agitation 300-500 rpm (under active D.O. control), no pH control, antifoam as required (Antifoam 204).
  • the fermentation progressed at 37° C. for 3 days and was harvested by first acidifying (HCl) the broth (pH 2.0) to facilitate the broth flow through the tubing. The reduced pH broth was then centrifuged at 16,000 ⁇ g for 20 minutes.
  • the fractionated ⁇ -PGA of Example 2 was further processed by ultrafiltration, using a 100,000 MWCO regenerated cellulose filter. As filtration progressed, a further M w reduction to 15,000 Da was achieved.
  • Example 1 Poly( ⁇ -glutamic acid) Purity.
  • the material prepared in Example 1 was examined for its purity. The results are shown in Table 2, and compared with a prior art material. The results show clearly that ⁇ -PGA in Example 1 is of superior purity.
  • Toxicity Studies of Native ⁇ -PGA Toxicity studies were performed, using purified ⁇ -PGA (1 ⁇ 10 6 Da material obtained in Example 1) in rat muscle (L6) and rat liver (H35) cell lines at concentrations ranging from 5 mg/L-0.5 g/L in Dulbecco's Modified Eagle's Medium (DMEM). Once cell lines were established, media exchanges were performed with DMEM containing ⁇ -PGA at the appropriate concentration. The L6 cell lines all differentiated normally and ⁇ -PGA did not interfere with differentiation into the elongated muscle form. Results from the H35 cell line study indicated again, no significant adverse effect on cell growth.
  • DMEM Dulbecco's Modified Eagle's Medium
  • Benzophenone was converted via borohydride reduction in alcohol solution to 1,2-bis(phenyl phenylmethoxy)ethane.
  • the resulting benzhydrol (1 equivalent) was subsequently condensed with a suitable bifunctional alcohol or diol (e.g., ethylene glycol, 10 equivalents) in the presence of methanesulfonic acid catalyst to afford, after chromatography the corresponding ether or diether.
  • a suitable bifunctional alcohol or diol e.g., ethylene glycol, 10 equivalents
  • PNET2 cells were infected with different multiplicities of infection (MOI) (0-200) of AdvNOS III or Adv-GFP; and 2) PNET2 cells were infected with 0, 10 or 20 MOI of Adv-NOS III or Adv-GFP, and treated with low, non-toxic concentrations of H 2 O 2 (8 ⁇ M), desferoxamine (0.1-2 mM), or DDC (200 ⁇ M).
  • H 2 O 2 provides a source of superoxide and free radicals.
  • Desferoxamine was added as it provides an in vitro model of hypoxic/ischemic injury, and treatment of PNET2 cells with 1-10 mM desferoxamine induces apoptosis.
  • DDC inhibits production of free radical scavenger agents. Viability was measured by the MTT assay. In addition to assaying viability, the degree to which the synthetic compounds inhibit NOS III-induced in situ apoptosis, DNA damage, activation of pro-apoptosis genes, and inhibition of cell survival genes was assessed.
  • PNET2 cells were maintained in Dulbecco's modified Eagle's medium (DMDM) supplemented with 0.9% glucose, 8 mM glutamine, 100 ⁇ M non-essential amino acids, and 10% fetal bovine serum.
  • DMDM Dulbecco's modified Eagle's medium
  • Subconfluent cultures seeded into 96-well plates (2 ⁇ 10 4 cells/well) were infected with recombinant Adenovirus vectors (Adv) that express a full-length cDNA encoding NOS III or green fluorescent protein (GFP) under control of a CMV promoter.
  • the cells were studied at 0, 24, 48, or 72 hours after infection. GFP and NOS III expression was verified by the microtiter immunocytochemical ELISA (see below).
  • Cell viability assays were measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, using cells seeded into 96-well plates.
  • the MTT assay is based on conversion of MTT to formazin by a mitochondrial enzyme.
  • the cells were incubated with 0.5 ⁇ g/ml of MTT solution prepared in phenol red-free DMEM. The plates were rinsed in PBS and the MTT formazin precipitate was eluted into 50 ⁇ l/well of 0.04 N HCl in methanol.
  • the absorbance was read at 540 nm, and background readings at 670 nm were subtracted. MTT absorbance values were linear with respect to cell density between 10 4 and 5 ⁇ 10 5 cells/well. Since the MTT assay measures both metabolic function (mitochondrial-based) and cell viability, a second method, the crystal violet assay, was used to assess cell density.
  • the crystal violet assay the cells were rinsed in phosphate buffered saline (PBS) and stained for 10 minutes at room temperature with crystal violet solution (0.05% crystal violet, 2% formalin, 10% methanol). After extensive rinsing in tap water baths, the plates were dried and the dye eluted with 200 ⁇ l/well of PBS containing 1% SDS. The absorbance was measured at 595 nm using an automated ELISA reader.
  • Apoptosis assays Several methods to detect apoptosis were used as there are now markers that detect very early, intermediate, and late changes preceding nuclear DNA fragmentation.
  • immunoreactivity for Annexin V screened using fluorescein-conjugated Annexin V. After incubation with FITC-conjugated Annexin V, the cells were fixed and stained with DAPI. Using an automated fluorescence reader, the relative abundance of Annexin V-positive cells (DAPI-positive cells as denominator) was assessed. For detecting nicked DNA, the cells were stained with antibodies to single-stranded DNA (Apostain) by the MICE assay.
  • peroxynitrite is a free radical generated by reaction of NO and superoxide. Peroxynitrite immunoreactivity was assessed by the MICE assay (see below).
  • MICE Microtiter Immunocytochemical ELISA
  • the MICE assay is a rapid method for objectively quantifying levels of immunoreactivity in cultured cells without the need for protein extraction, gel electrophoresis, or cell counting.
  • the MICE assay differs from the cellular ELISA in that it incorporates a correction for cell density into the procedure, thereby permitting comparisons of protein expression following different treatments, even if the effect of the treatment includes cell death or proliferation.
  • the MICE assay measures levels of protein expression, whereas cellular ELISAs are designed to detect surface immunoreactivity. Detailed methods describing this assay were described recently (de la Monte S.
  • Antibody binding was detected with horseradish peroxidase conjugated anti-mouse IgG and TMB soluble peroxidase substrate (100 ⁇ l per well). Color development was stopped prior to saturation by adding 100 ⁇ l 1 M H 2 SO 4 per well. The absorbance was measured at 450 nm using an automated microplate reader.
  • the absorbance at 650 nm was measured, using an automated microplate reader.
  • the MICE index was calculated from the ratio of the absorbances for immunoreactivity and Coomassie blue labeling (cell density). The means and standard deviations obtained for 8 replicate culture wells were used in the data analysis.
  • levels of NOS III, GFP, p53 (pro-apoptosis), Bcl-2 (survival), and Bax (pro-apoptosis) were measured. Positive and negative controls for antibody binding were included in all assays.
  • Cerebral cortex tissue harvested from 16-18 day old rat fetuses (Sprague-Dawley) was incubated for 10 minutes in calcium-free and magnesium-free Hanks balanced salt solution (CMF-HBSS), followed by digestion in 0.25% trypsin/CMF-HBSS for 30 minutes at 37° C. After washing in Eagle's basal medium containing 1% ovalbumin, the cells were dissociated by trituration.
  • CMF-HBSS calcium-free and magnesium-free Hanks balanced salt solution
  • the cells were suspended in Eagle's basal medium plus N1 supplement (defined medium with 0.83 ⁇ M insulin, 0.062 ⁇ M transferrin, 10 mM putrescine, 0.02 ⁇ M progesterone, and 0.03 ⁇ M selenite) and seeded at a density of 5 ⁇ 10 4 cells/well of 96-well plates.
  • the wells were pre-coated with polyornithine (0.1 mg/ml poly-(L-ornithine) in 15 mM borate buffer, pH 8.4 for 2 h at room temperature), and after rinsing with DMEM, adding a coating of laminin (1 ⁇ g/ml; overnight) to promote cell adhesion and neurite outgrowth. Because of the developmental stage, the majority of cells were neuronal.
  • Test Results of Neuroprotective Agents are as follows: When the changes in neuronal viability were measured as a function of ⁇ -PGA concentration it was observed that ⁇ -PGA delivered very significant rescue efficacy to neuronal cultures that had previously been subjected to oxidative stress (40 mM H 2 O 2 ). In these experiments, primary cortical neuron cultures were pre-treated with various dilutions of ⁇ -PGA one day prior to being subjected to the oxidative injury. The cell viability was measured using the crystal violet assay one day after the oxidative injury. Oxidant-exposed cultures exhibited a 40% loss of viability and mitochondrial function.
  • FIGS. 6 and 8 show changes in neuronal viability as a function of arabinogalactan concentration: rescue efficacy of arabinogalactan delivered to neuronal cultures subjected to oxidative stress (40 mM H 2 O 2 ). Viability is expressed as percentage change relative to cultures treated only with the oxidant. Primary cortical neuron cultures were pre-treated with various dilutions of arabinogalactan 1 day prior to being subjected to oxidative injury.
  • Diphenylamine pretreatment resulted in less pronounced neuronal rescue at similar concentrations. See FIG. 9 which shows changes in neuronal viability as a function of diphenylamine concentration in tests similar to those described above. Diphenylamine pretreatment produced a modest increase in viability.
  • the Mt function was assessed by the MTT assay (described above) and changes in Mt function were calculated relative to control cultures not exposed to neuroprotective candidates.
  • the graphs illustrate the viability change relative to cultures infected only with Adv-NOS III. Points falling below the abscissa reflected further cell loss, while points above the abscissa indicated improved viability. Standard deviations calculated for 8 replicate cultures were below 10% in all instances.
  • the rescue efficacy was assessed for neuroprotective candidate treatment for neuronal cultures subjected to oxidative stress via nitric oxide synthase 3 (NOS III) over-expression.
  • FIG. 10 shows that ⁇ -PGA treatment again resulted in increased Mt function (up to 320%) in un-infected cultures.
  • FIG. 12 shows that arabinogalactan treatment resulted in increased Mt function (up to 60%) in un-infected cultures. With increasing MOIs (0-100), arabinogalactan exerted neuroprotective effects.
  • FIG. 11 shows that dichlorobenzhydrol phenoxyamine provided less pronounced neuroprotection against NOS III over-expression under the experimental conditions.
  • Novel Neuroprotective Agents This invention relates to compounds represented by the general formulas (I-IV, XII and other compounds described herein) that have a nitric oxide synthase (NOS) inhibiting effect or neuroprotective effect and thereby prove effective in ameliorating, preventing or reversing degenerative or neurological diseases and disorders resulting from excessive nitric oxide (NO) or its metabolites, including cerebrovascular diseases, such as cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction (atherothrombotic infarction, lacunar infarction and cardiogenic embolism), transient ischemic attack and cerebral edema, traumatic brain injury, spinal injury, pain, such as headache (migraine, tension headache, cluster headache, chronic paroxysmal headache), neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Pick's disease, Creutzfield-Jacob disease, Amyotrophic Lateral Sclerosis (ALS), Multi-infarct
  • NOS ni
  • Compounds of the general formulas I-IV and XII and the other compounds described herein and the pharmaceutical compositions derived from these compounds can also be used for the post-acute therapeutic treatment of a variety of neurological conditions in which various cell types of the nervous system are degenerated and/or have been damaged as a result of injuries or exposures.
  • the present neuroprotective compounds can be used for the treatment of resulting conditions, in which damage to cells of the nervous system has occurred due to surgical interventions, infections, exposure to toxic agents, tumors, nutritional deficits or metabolic disorders.
  • the present neuroprotective compounds can be used for the treatment of the sequelae of injuries, dystrophy or degeneration of the neural retina (retinopathies) and peripheral neuropathies, such as diabetic neuropathy and/or the peripheral neuropathies induced by toxins.
  • the present neuroprotective compounds can also be used in combination with surgical implantations of tissues and/or prostheses for the treatment of Alzheimer's disease or other neurological disorders and/or malfunctions in which implantation is indicated.
  • the prophylactic and therapeutic agents of the present invention can be optionally provided in any dosage form known in the art that can be manufactured by a known pharmaceutical technology that comprises, for example, mixing or dissolving the active compound with a pharmaceutically acceptable carrier or vehicle.
  • a dosage form known in the art that can be manufactured by a known pharmaceutical technology that comprises, for example, mixing or dissolving the active compound with a pharmaceutically acceptable carrier or vehicle.
  • the oral dosage forms for use in humans include powders, granules, tablets, capsules, syrups, and other liquid preparations.
  • Powders, granules, tablets and the like can be manufactured using optional pharmaceutically suitable carriers that are suitable for solid preparations, such as excipients (e.g., starch, glucose, fructose, sucrose, lactose, etc.), lubricants (e.g., magnesium stearate, calcium stearate, etc.), disintegrators (e.g., starch, crystalline cellulose, etc.), binders (e.g., starch, gum arabic, etc.), and so forth.
  • excipients e.g., starch, glucose, fructose, sucrose, lactose, etc.
  • lubricants e.g., magnesium stearate, calcium stearate, etc.
  • disintegrators e.g., starch, crystalline cellulose, etc.
  • binders e.g., starch, gum arabic, etc.
  • Such solid preparation may be optionally coated with a coating agent (e.g., gelatin, sucrose, etc.) or an enteric coating (e.g., hydroxypropyl methylcellulose phthalate, methacrylic copolymers, shellac, etc.), so that the active compound may be released specifically in the intestines.
  • a coating agent e.g., gelatin, sucrose, etc.
  • an enteric coating e.g., hydroxypropyl methylcellulose phthalate, methacrylic copolymers, shellac, etc.
  • various additives such as stabilizers (e.g., sodium edetate etc.), suspending agents (e.g., gum arabic, carmellose, etc.), corrigents (e.g., simple syrup, glucose, etc.), flavors, etc. can be appropriately added.
  • the dosage form for non-oral systemic administration includes injections, suppositories, etc.
  • Injections can be manufactured by using solvents (e.g. water for injection, etc.), stabilizers (e.g., sodium edetate etc.), isotonizing agents (e.g., sodium chloride, glycerol, mannitol, etc.), pH control agents (e.g., hydrochloric acid, citric acid, sodium hydroxide, etc.), suspending agents (e.g., methylcellulose, sodium carboxymethyl cellulose, etc.), and other suitable additives.
  • solvents e.g. water for injection, etc.
  • stabilizers e.g., sodium edetate etc.
  • isotonizing agents e.g., sodium chloride, glycerol, mannitol, etc.
  • pH control agents e.g., hydrochloric acid, citric acid, sodium hydroxide, etc.
  • suspending agents e.g., methylcellulose, sodium carboxymethyl cellulose, etc.
  • a suppository base e
  • the prophylactic and therapeutic drug of the present invention is useful for the prevention and treatment of neurodegenerative disorders and diseases in mammals (e.g., human, gerbil, rat, mouse, rabbit, cow, pig, dog, cat, and the like).
  • the dosage of the compounds of formula (I-IV), the other compounds described herein or pharmaceutically acceptable salts thereof according to the present invention is dependent on the target disease, clinical state and other conditions of patients, administration route, and other factors. Specific dosages ranges can be determined by routine dose titration experiments. Generally speaking, the objective effect can be achieved in a general dose of 0.001-1000 mg/kg of body weight and preferably 0.01-500 mg/kg of body weight.
  • the neuroprotective agents of the present invention can be used in conjunction with other active ingredients.

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US20060189910A1 (en) * 2001-02-16 2006-08-24 Kci Licensing, Inc. Biocompatible wound dressing
US20070099827A1 (en) * 2003-11-19 2007-05-03 Kazumichi Uotani Sialogogue, oral composition and fool product containing the same
US20100093935A1 (en) * 2008-10-15 2010-04-15 Nitto Denko Corporation Method of preparing polyglutamate conjugates
US7700819B2 (en) 2001-02-16 2010-04-20 Kci Licensing, Inc. Biocompatible wound dressing
CN101255404B (zh) * 2008-02-26 2010-12-15 新疆农业科学院微生物应用研究所 一种产麻黄碱的细菌及其生产的麻黄碱
US20110144315A1 (en) * 2009-12-16 2011-06-16 Nitto Denko Corporation Controlled synthesis of polyglutamic acid
US20110217725A1 (en) * 2008-10-24 2011-09-08 Kuraray Co., Ltd. Cell culture kit, screening method, and method of manufacturing cell culture kit
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US20120207766A1 (en) * 2009-07-23 2012-08-16 Athena Soulika Intracellular toll-like receptors pathways and axonal degeneration
WO2012172090A1 (fr) * 2011-06-17 2012-12-20 Ludwig Aigner Prénylflavonoïdes cycliques de chromane pour intervention médicale lors de troubles neurologiques
WO2015035308A3 (fr) * 2013-09-06 2015-10-29 The University Of Montana Méthode de réduction de la mort des cellules neuronales avec des halogénoalkylamines
CN106770839A (zh) * 2017-03-02 2017-05-31 浙江工业大学 一种山豆根中黄酮类化合物的提取检测方法
US9937144B2 (en) 2013-01-30 2018-04-10 The Johns Hopkins University Treatment of drug abuse by preventing GAPDH nitrosylation
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WO2007062186A2 (fr) * 2005-11-21 2007-05-31 The Board Of Trustees Of The University Of Alabama For And On Behalf Of The University Of Alabama Procedes utilisant des composes de petites molecules a des fins de neuroprotection
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US20060189910A1 (en) * 2001-02-16 2006-08-24 Kci Licensing, Inc. Biocompatible wound dressing
US7700819B2 (en) 2001-02-16 2010-04-20 Kci Licensing, Inc. Biocompatible wound dressing
US7763769B2 (en) 2001-02-16 2010-07-27 Kci Licensing, Inc. Biocompatible wound dressing
US8735644B2 (en) 2001-02-16 2014-05-27 Kci Licensing, Inc. Biocompatible wound dressing
US8084664B2 (en) 2001-02-16 2011-12-27 Kci Licensing, Inc. Biocompatible wound dressing
US8163974B2 (en) 2001-02-16 2012-04-24 Kci Licensing, Inc. Biocompatible wound dressing
US20070099827A1 (en) * 2003-11-19 2007-05-03 Kazumichi Uotani Sialogogue, oral composition and fool product containing the same
US7910089B2 (en) * 2003-11-19 2011-03-22 Meiji Seika Kaisha, Ltd. Sialogogue, oral composition and food product containing the same
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US20100093935A1 (en) * 2008-10-15 2010-04-15 Nitto Denko Corporation Method of preparing polyglutamate conjugates
US10836996B2 (en) 2008-10-24 2020-11-17 Corning Incorporated Cell culture kit, screening method, and method of manufacturing cell culture kit
US20110217725A1 (en) * 2008-10-24 2011-09-08 Kuraray Co., Ltd. Cell culture kit, screening method, and method of manufacturing cell culture kit
US20120207766A1 (en) * 2009-07-23 2012-08-16 Athena Soulika Intracellular toll-like receptors pathways and axonal degeneration
CN102666566A (zh) * 2009-12-16 2012-09-12 日东电工株式会社 聚谷氨酸的受控合成
US20110144315A1 (en) * 2009-12-16 2011-06-16 Nitto Denko Corporation Controlled synthesis of polyglutamic acid
WO2012172090A1 (fr) * 2011-06-17 2012-12-20 Ludwig Aigner Prénylflavonoïdes cycliques de chromane pour intervention médicale lors de troubles neurologiques
US9527860B2 (en) 2011-06-17 2016-12-27 Ludwig Aigner Chromane-like cyclic prenylflavonoids for the medical intervention in neurological disorders
US9956199B2 (en) 2011-06-17 2018-05-01 Ludwig Aigner Chromane-like cyclic prenylflavonoids for the medical intervention in neurological disorders
EP3202398A1 (fr) * 2011-06-17 2017-08-09 Ludwig Aigner Chromane-similaires prénylflavonoïdes cycliques pour l'intervention médicale lors de troubles neurologiques
CN102268389A (zh) * 2011-07-07 2011-12-07 江南大学 一种甲基营养芽孢杆菌及其发酵生产γ-聚谷氨酸的方法
US9937144B2 (en) 2013-01-30 2018-04-10 The Johns Hopkins University Treatment of drug abuse by preventing GAPDH nitrosylation
WO2015035308A3 (fr) * 2013-09-06 2015-10-29 The University Of Montana Méthode de réduction de la mort des cellules neuronales avec des halogénoalkylamines
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US10849865B2 (en) 2013-09-06 2020-12-01 The University Of Montana Method of reducing neuronal cell death with haloalkylamines
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